16beta-alkylthio-17beta-hydroxy-steroids and 17-acylates thereof



United States Patent 3,378,548 1Gfl-ALKYLTHIO-17fi-HYDROXY-STEROIDS AND l7-ACYLATES THEREOF Taichiro Komeno, Osaka, and Norio Tokutake, Kobe, Japan, assignors to Shionogi & Co., Ltd., Osaka, Japan N0 Drawing. Filed Mar. 1, 1963, Ser. No. 262,213 'Claims priority, application Japan, Mar. 20, 1962, 37/ 11,348 14 Claims. (Cl. 260-43955) The present invention relates to steroid and production thereof. More particularly, it relates to 16B-alkylthio- 17fl-hydroxy-steroid and its 17-acylate and production thereof.

The process of the present invention is substantially representable by the following scheme:

wherein R is a lower alkyl group (e.g. methyl, ethyl, propyl, butyl, pentyl, hexyl) and R is a lower alkanoyl group (e.g. acetyl, propionyl, butyryl, valeryl).

The process is generally applicable to the conversion of a 16B-alkylthio-17-oxo-steroid into the corresponding 16fl-alkylthio-17fl-hydroxy-steroid or its acylate. Especially, its application to the 16,8-alkylthio-17-oxo-steroid represented by the formula:

. wherein R has the same significance as designated above and a substituent(s) such as hydroxyl, lower alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy), oxo, lower alkylenedioxy (e.g. ethylendioxy, propylenedioxy), lower alkyl (e.g. methyl, ethyl, propyl) and lower alkoxy (e.g. methoxy, ethoxy, propoxy) and less than 4 double bond(s) can be present on the A-ring and the A- and B-rings, respectively, gives a 1-6,B-alkylthio-17B-hydroxy-steroid or its acylate represented by the formula:

wherein R" is a hydrogen atom or a lower alkanoyl group (e.g. acetyl, propionyl, butyryl, valeryl), R has the same significance as designated above and a substituent(s) such as hydroxyl, lower alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy), oxo, lower alkylenedioxy (e.g. ethylenedioxy, propylenedioxy), lower alkyl (e.g. methyl, ethyl, propyl) and lower alkoxy (e.g. methoxy, ethoxy, propoxy) and less than 4 double bond(s) can be present on the A-ring and the A- and B-rings, respectively, which may possess physiological activities. Accordingly, the process of the present invention will be hereinafter illustrated taking its application to the said 16,6-alkylthio-l7- oxo-steroid (I) as an example. However, it should be understood that the scope of the present invention is not Patented Apr. 16, 1968 limited only to the application of the process to the said 16fl-alkylthio-17-oxo-steroid (I).

When the process of the present invention invention is applied to the l6fl-alkylthio-17-oxo-steroid (I), the conversion may be substantially represented by the formula:

(II) (III) wherein R and R each has the same significance as designated above and a substituent(s) such as hydroxyl, lower alkanoyloxy (e.g. acetyloxy, propionyloxy, butyryloxy), oxo, lower alkylenedioxy (e.g. ethylenedioxy, propylenedioxy), lower alkyl (e.g. methyl, ethyl, propyl) and lower alkoxy (e.g. methoxy, ethoxy, propoxy) and less than 4 double bond(s) can be present on the A-ring and the A- and B-rings, respectively. In this connection, it would be understood that the foregoing formulae show the substantial order of the steps in the production, modifications and equivalents-including possible detours-being omitted. Thus, when the free oxo group, if any, present on the A-ring is unfavorably affected in the course of the process, the group is required to be properly protected prior to the execution of the reaction. For instance, the direct conversion of 16-ethylthio-4-androstene-3,17-dioue into 16,8-ethylthio-l7B-hydroxy-4-androsten-3-one can be unsuccessfully accomplished by the application of reduction as shown above. Therefore, the latter is actually produced by reducing 3,3-ethylenedioxy-16 8-ethylthio-5 (6)- androsten-17-one to 3,3-ethylenedioxy 16,8 ethylthio- 5 (6)-androsten-17/i-ol, followed by deketalation.

The starting materials, 16fi-alkylthio-17-oxo-steroids (I) may be exemplified as follows:

16,6-methylthioestrone,

16/3-ethylthioestrone,

lfili-propylthioestrone,

lb-butylthioestrone,

l6fl-ethylthioestrone 3-methyl ether,

l6fl-ethylthioestrone 3-ethyl ether,

1 6/3-b utylthioestrone S-methyl ether,

l-methyll GB-ethylthioestrone,

l-Inethyl-IGfi-ethylthioestrone B-methyl ether,

l-methyl-lGB-butylthioestrone 3-methyl ether,

4-methyl-16fi-methylthio-1,3,5 10 -estratrienl7-one,

4-methyl-16fl-ethylthio-1,3,5 10 -estratrien- 17-one,

4-methyl- 1-6fi-butylthio-1,3,5 10) -estratrien- 17-one,

3 a-hydroxy-1613-ethylthio-S/R-androstan-17one,

3B-hydroxy-16,8-ethylthio-5u-androstan-17-one,

3,3-hydroxy-16B-ethylthio-5 6 -androsten-17-one,

3a-hydroxy-16fi-ethylthio-5 6 -androsten- 17-one,

16B-ethylthio-5fl-androstane-3,17-dione,

1GB-methylthio-Sa-andmstane-3,17-di0ne,

-ethylthio-4-androstene-3,17-dione,

3,3-ethylenedioxy-16,8-ethylthio-5 (6 )-androsten-l7- one, etc.

These l6fl-alkylthio-17-oxo-steroids (I) are unknown compounds and can be prepared by reacting the corresponding 16ozor 16fl-halogeno-l7-oxo-steroids, which are generally known [e.g. Fried et al.: US. Patents Nos. 2,857,403 and 2,831,872; Ellis et al.: J. Chem. 800., p. 800 (1958); Fajkos et al.: Chemical Abstracts, vol. 53, p. 4349 (1959); Johnson et al.: J. Am. Chem. Soc., vol. 79, p. 2005 (1957)], with alkali metal lower alkylmercaptide in an inert organic solvent medium at a temperature from room temperature to rellux temperature.

According to the process of the present invention, the 16fi-alkylthio-17'oxo-steroid (I) is reacted with a reducing agent such as an alkali metal hydride complex (e.g. lithium aluminum hydride, sodium borohydride) and a combination of an alkali metal (e.g. metallic sodium, metallic potassium) with a lower alkanol (e.g. methanol, ethanol) to give the 16B-alkylthio-17fi-hydroxy-steroid (II). The reaction may be performed according to the procedure ordinarily adopted en the use of each of the said reducing agents. For instance, when lithium aluminum hydride is employed, the reaction is executed by treating the 16,8-alkylthi-17-oxo-steroid (II) with the reducing agent in an inert organic solvent medium (e.g. ether, tetrahydrofuran, dioxane) at room temperature to 30 C.). The above-prepared l6fl-alkylthio-l7fl-hydroxy-steroid (II), if necessary, may be subjected to acylation on the 17-hydroxyl group by a per se conventional procedure to give the 16,8-alkylthio-17fl-acyloxysteroid (III). For instance, the acylation can be readily carried out by treating the 16B-alkylthio-17fl-hydroxysteroid (II) with a lower alkanoic anhydride (e.g. acetic anhydride, propionic anhydride) and an organic base (e.g. pyridine, picoline) while refluxing.

The thus-produced 16;8-alkylthio-l7fl-hydroxy-steroid (II) and its acylate (III), are specifically exemplified as follows:

16fi-methylthioestradiol,

16;.8-ethy1thioestradiol,

16/3-propylthioestradiol,

16fi-butylthioestradiol,

16fl-ethylthioestradiol methyl ether,

l6fl-ethylthi0estradiol methyl ether l7-acetate,

l6/3-ethylthioestradiol ethyl ether,

l6fl-butylthioestradiol methyl ether,

l-methyl-lfifl-ethylthioestradiol,

l-methyl-l6/3-ethylthioestradiol methyl ether,

l-methyl-l6li-buty1thioestradiol methyl ether 17-acetate,

4-methyl- 1 6,8-methy1thio- 1,3 ,5( 10 )-estratrien- 17,8-01,

4-methyl-16;3-ethy1thio-1,3,5 10) -estratrien-17B-01 17-acetate,

4-methyl-16fl-butylthi0-1,3,5 10)-estratrien-17fl-0l 17-propionate,

3a-hydroxy-16B-ethylthio-5 3-androstan-175-01,

3B-hydroxy-l6fi-ethylthio-5a-androstan-175-01,

3 B-hydroxy- 1 6fi-ethylthio-5 6 -androsten- 175-01 3-acetate,

3 B-hydroxy-16fl-ethylthio-5 (6)-androsten-l7}9-ol 3,17-diacetate,

3 a-hydroxyl 6 3-ethylthio-5 6 -androsten-17B-ol 3-acetate,

1GB-ethylthio-175-hydroxy-5 8-androstan-3-one 17-acetate,

l6B-methylthio-l7/3-hydroxy-5a-androstan-3-one 16fiethylthio-17li-hydroxy-4-androsten-3-one,

l6fl-butylthio-17/3-hydroxy-4-androsten-3-one 17-acetate,

3,3-ethylenedioxy-16/3-ethylthio-5 6 )-androsten-l 719-01 17-acetate, etc.

These products (IV) generally show a variety of physiological activities. For instance, 16B-ethylthioestradiol methyl ether produced significant inhibition of gonadotrophin secretion without any concomitant androgenic response, when orally administered to female-castrated male parabionts of mice at a total dose of 1 milligram. The said substance also showed lipid shifting activity in the test using rats and uterotropic activity in the test using mice. Further, for instance, 16 3-ethylthio-17/3-hydroxy-4-androsten-3-one showed Na-retaining activity by itself, when subcutaneously administered to rats at a total dose of 5 milligrams. The other products possess the similar physiological activities. Accordingly, they are useful as artificial hormonic agents.

The following examples set forth illustratively presentlypreferred embodiments of the invention. In these examples, the abbreviations are intended to have conventional meanings: e.g. g., gram(s); mg., milligram(s); ml., millilitre(s); C., degrees centigrade.

Example 1 O I I $0211;

OH SC2H5 O C 0 CH3 I s onr,

CHaO

A solution of l6B-ethylthioestrone methyl ether (500 mg.) in anhydrous tetrahydrofuran (40 ml.) is added dropwise to a suspension of lithium aluminum hydride (250 mg.) in anhydrous ether (50 ml.) at room temperature (15 to 30 C.). The resultant mixture is refluxed for 2.5 hours. To the reaction mixture, there is added water and then shaken with ether. The ether extract is washed with water, dried and evaporated. The residue is crystallized from ethanol to give 16B-ethylthioestradiol methyl ether (450 mg.) as white scales melting at 127.5 to 128.5 C.

[a] +35.3 (CHCl X523? mu(e): 279 (2,110), 287 (1,900). 11,1122" 3500-3460 cm."

Analysis.Calcd. for C H O S: C, 72.78; H, 8.72; S, 9.25. Found: C, 73.02; H, 8.90; S, 9.19.

A solution of the above obtained 16B-ethy1thioestradiol methyl ether (100 mg.) in pyridine (1 ml.) and acetic anhydride (1 ml.) is refluxed for 2 hours. The reaction mixture is condensed under reduced pressure. The residue is crystallized from a mixture of ether and methanol and recrystallized from a mixture of acetone and hexane to give 16B-ethylthioestradiol methyl ether 17-acetate (90 mg.) as crystals melting at 82.5 to 83.5 C.

0.]? +900 (01101, my m;r(e): 208 (24,200 270 (2,120), 287.5 (1,080 vggy 1740, 1614, 1503, 1239 em."

Analysis.Calcd. for C H O S: C, 71.10; H, 8.30; S, 8.33. Found: 'C, 71.10; H, 8.41; S, 8.28.

The starting material of this example, 16fi-ethy1thioestrone methyl ether, is prepared from 16a-bromoestrone 6 methyl ether [Johnson et al.: J. Am. Chem. Soc., vol. 79, p. 2005 (1957)] according to the following scheme:

C(Hq O C aO Potassium ethylmercaptide Example 3 CHaO OH 0 SCQH; SCzH;

SC2H5 Example 2 To a solution of 3.,3-ethylenedioxy-l6p-ethylthio-5(6)- androsten-17-one (788 mg.) in ethanol m1), there is added sodium borohydride (200 mg.), and the resultant mixture is stirred for 2 hours at room temperature (15 to 30 0.). Water is added to the reaction mixture and OH 35 shaken with chloroform. The chloroform extract is washed with water, dried and evaporated. The residue is crystallized from ethanol to give 3,3-ethylenedioxy-1619-ethyl- 504E thio-5(6)-androsten-17fl-ol (568 mg.) as long needles melting at 203 to 205 C. 0.1%, 72.1i2 01101, P222 3510, 1672 01117 Analysis.-Calcd. for C H O S: C, 70.36; H, 9.24; S, OH; 8.17. Found: C, 70.15; H, 9.23; S, 8.13.

The starting material of this example, 3,3-ethy1enedioxy-16B-ethylthio-5 (6)-androsten-17-one, is prepared A Solution of l6t3-blltylthioestl'one methyl ether from 16 3-bromo-4-androstene-3,17-dione [Fajkos et aL: a) in anhydrous ether is added dropwise e Chemical Abstracts, vol. 53, p. 4349 1959 according suspension of lithium aluminum hydride (100 mg.) in t th f ll i h anhydrous ether (10 ml.) at room temperature (15 to 30 C.). The resultant mixture is refluxed for 3 hours. To the 0 reaction mixture, there is added water and then shaken I with ether. The ether extract is washed with water, dried and evaporated. The residue is crystallized from a mixture of ether and hexane (1:3) to give 16,6-butylthioestradiol i gigf i gg methyl ether (168 mg.) as white plates melting at 74.5 sulfonic acid to 75.5" c. O

o 1260, 1240 cm.-

Br Analysis.Calcd. for C H O S: C, 73.75; H, 9.15; S, 8.56. Found: C, 73.56; H, 9.13; S, 8.56.

The starting material of this example, IGB-butylthio- Sodium ethylmercaptide estrone methyl ether, is prepared from lfia-bromoestrone methyl ether according to the following scheme:

B SC2H5 r Potassium butylmercaptide CHaO --O EXAMPLE 4 (RH OH S 2 5 S z r O C O CH:

Example 4 3,3-ethylenedioxy 16B ethylthio-(6)-androsten-17fl- 01 (568 mg.) is refluxed with p-toluenesulfonic acid hydrate (60 mg.) and acetone (20 ml.) for 2 hours. Water is added to the reaction mixture. The separated crystals are collected by filtration and recrystallized from aqueous methanol to give 16p-ethy1thio-i7/3-hydroxy-4-androsten- 3-one (509 mg.) as needles melting at 147 to 149 C.

[0.15, +392 :l;2 (01101,). 111,. (e): 242 (17,800). 1 222 3515, 1676, 1622 emr Analysis.Calcd. for C H O S: C, 72.36; H, 9.25; S, 9.20. Found: C, 72.31; H, 9.30; S, 9.36.

The above obtained 16,8-ethylthio-17p-hydroxy-4-androsten-3-one (436 mg.) is mixed with pyridine (2 ml.) and acetic anhydride (1 ml.) and refluxed for 2 hours. The reaction mixture is condensed under reduced pressure. The residue is crystallized from aqueous methanol to give 165- ethylthio-17p-hydroxy-4-androsten-3-one 17-acetate (368 mg.) as needles melting at 132 to 134 C.

[etl'fg +1036 :l:2 (CHOl A3135? my. (6): 241 (18,000). 1 23? 1736, 1680, 1665 (shoulder), 1614, 1233, 1059, 1020 em."

Aethnnal max.

Example 5 SCzHl C aO CHsO

O C 0 CH3 SCZHE CHsO A solution of l-tmethyl-1-6/3-ethylthioestrone methyl ether (3 g.) in ether ml.) is added dropwise to a suspension of lithium aluminum hydride (1.5 g.) in ether ml.). The resultant mixture is refluxed for 3 hours. To the reaction mixture, there is added water and then shaken with ether. The ether extract is washed with water, dried and evaporated whereby 1-methyl-16B-ethylthioestradiol methyl ether (2.8 g.) is a viscous substance.

A solution of the above obtained I-methyl-lG/S-ethyL thioestradiol methyl ether (2.8 g.) in pyridine (20 ml.) and acetic anhydride (15 ml.) is refluxed for 2 hours. The reaction mixture is condensed under reduced pressure. The residue is dissolved in petroleum ether and chromatographed on alumina. The eluate with a mixture of petroleum ether and benzene (6:4-1:9) is crystallized from methanol to give l-methyl-IGB-ethylithio-estradiol methyl ether 17-acetate (2.20 g.) as plates melting at 86.5 to 87 C.

[01],? +149.9 (CHOI 11221? 1736, 1237 cm.-

Analysis.-Calcd. for C I-I O S: C, 71.61; H, 8.51; S, 7.95. Found: C,71.49; H, 8.54; S, 7.68.

The starting material of this example, 1-methyl-l65- ethylthioestrone methyl ether is prepared from testosterone propionate according to the following scheme:

OCOCzHr Bromine Acetic acid Collldlne o O C 0 C211;

/ Acetic anhydride p-Toluenesulionie acid Palladium-carbon 011.000 Hydmgm O C 0 Call (1) Potassium hydroxide Methanol CHSCOO (2) Dimethyl sulfate Potassium hydroxide (i)H I r l Chromic acid CHaO Isopropenyl acetate sulfuric acid Bromine cm WWW Sodium mercaptide CHaO In the similar manner, there can be obtained other 16;?- lower alkylthioestradiol lower alkyl ether, 16,3-lower alkyl-thioestradiol lower alkyl ether 17-lower alkanoate,

3,3-lower alkylenedioxy-16B-lower alkylthio-5(6)-androsten-17-ol,16,B-lower alkylthio-l7fl-hydroxy-4-androsten- 3-one, 16fl-lower alkylthio-17 3-hydroxy-3-androsten-3- one 17-lower alkanoate, l-lower alkyl-lp-lower alkylthioestradiol lower alkyl ether and l-lower alkyl-16fllower alkylthioestradiol lower alkyl ether l7-lower alk'anoate.

What is claimed is:

1. A steroid represented by the formula:

on" g: s1; Z

wherein R is lower alkyl, R" is a member selected from the group consisting of hydrogen and lower alkanoyl and Z is a ring system selected from the group consisting of lower alkyl l lower adm t-Ow lower alkyd-0m lower alkzinoyl0 I lower alkanoyl-O-Q and (llfl wherein R=lower alkyl.

13. A compound of the formula I s R wherein R=1ower alkyl.

14. A compound selected from the group consisting of compounds of the formula wherein R is lower alkyl and R" is selected from the group consisting of hydrogen and lower alkauoyl.

References Cited Fajkos et 211.: Chemical Abstracts, vol. 53 (1959), p. 4349.

ELBERT ROBERTS, Primary Examiner. 

1. A STEROID REPRESENTED BY THE FORMULA: 